Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes.
The formation and deposition of monosodium urate (MSU) microcrystals in articular and periarticular tissues is the causative agent of acute or chronic inflammatory responses known as gouty arthritis. Mononuclear phagocyte activation is involved in early triggering events of gout attacks. Because stimulated mononuclear phagocytes can constitute an important source of the inducible isoform of cyclooxygenase (COX-2), we evaluated the effects that proinflammatory microcrystals might have on COX-2 protein expression in crystal-stimulated monocytes. We found that MSU crystals, but not calcium pyrophosphate dihydrate (CPPD) crystals, induced COX-2, which correlated with the synthesis of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2). Crystal-induced de novo synthesis of COX-2 was dependent on transcriptional and translational events. Inhibition of tyrosine phosphorylation, by herbimycin A, blocked crystal-induced COX-2. Similarly, an inhibitor of the p38 mitogen-activated protein kinase, SB 203580, inhibited the stimulation of COX-2. Colchicine inhibited crystal-induced COX-2. In all cases, prostanoid synthesis was concomitantly inhibited. Taken together, these results implicate COX-2 in the development of MSU-induced inflammation.
Pouliot
M
M
Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia.
James
M J
MJ
McColl
S R
SR
Naccache
P H
PH
Cleland
L G
LG
D016227:Benzoquinones; D003078:Colchicine / Q000494:pharmacology; D003460:Crystallization; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006074:Gout Suppressants / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000097:blood; D007700:Kinetics; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D009000:Monocytes / Q000201:enzymology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000097:blood; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D013928:Thromboxane A2 / Q000096:biosynthesis; D014527:Uric Acid / Q000494:pharmacology*
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D006074:Gout Suppressants; D007527:Isoenzymes; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D011809:Quinones; D017828:Rifabutin; D019000:Phosphotyrosine; D014527:Uric Acid; D013928:Thromboxane A2; C020754:herbimycin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D015232:Dinoprostone; D003078:Colchicine